bims-nenemi Biomed News
on Neuroinflammation, neurodegeneration and mitochondria
Issue of 2025–07–06
23 papers selected by
Marco Tigano, Thomas Jefferson University
  1. Ionizing radiation triggers the release of mitochondrial DNA into the cytosol as a signal of mitochondrial damage.
  2. Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
  3. MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
  4. A constricted mitochondrial morphology formed during respiration.
  5. mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
  6. Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
  7. Autoregulation of the real-time kinetics of the human mitochondrial replicative helicase.
  8. Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
  9. Structural-functional characterization of the MIRO1-TRAK1 complex.
  10. An integrative modelling approach to the mitochondrial cristae.
  11. The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
  12. Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
  13. TRBP modulates RLR signaling by inhibiting PKR-mediated antiviral stress granule formation.
  14. High-throughput screening of E3 ubiquitin ligases identifies TRIM48 as a novel negative regulator of RIG-I signaling.
  15. Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.
  16. Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.
  17. Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
  18. Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
  19. The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
  20. Human FASTK preferentially binds single-stranded and G-rich RNA.
  21. Cardiac Myocyte Cytosolic Self-DNA Contributes to the Pathogenesis of Desmoplakin-Cardiomyopathy.
  22. P-glycoprotein expression skews mitochondrial dye measurements in T cells.
  23. WSTF nuclear autophagy regulates chronic but not acute inflammation.
  1. Sci Rep. 2025 Jul 02. 15(1): 23191
    Ionizing radiation triggers the release of mitochondrial DNA into the cytosol as a signal of mitochondrial damage.
    Tsutomu Shimura, Yui Takahashi, Chihiro Saito, Riko Maida, Megumi Sasatani, Tatsuki Kunoh, Akira Ushiyama.
      Inflammatory responses are crucial for repairing radiation-induced tissue damage. Excessive tissue remodeling in response to severe tissue injury causes chronic inflammation associated with various diseases including cardiovascular disease and cancer. Fibroblasts are major components of the stroma and play key roles in tissue remodeling. However, causes of inflammatory response activation remain unclear. This study focused on cytosolic mitochondrial DNA (mtDNA) release and its role in inflammation following irradiation. Cytosolic mtDNA leakage increased 3 h after irradiation of normal human fibroblasts and persisted for at least 7 days. H2O2 treatment of fibroblasts increased reactive oxygen species (ROS) levels, the number of cytosolic DNA per cell, and the number of senescent cells, indicating that ROS trigger cytosolic DNA release in association with cellular senescence. The cytosolic mtDNA was then recognized by the DNA sensor cyclic GMP-AMP synthase (cGAS), activating the cGAS/stimulator of interferon genes (STING) signaling pathway. DNA-PK and AMPK inhibitors prevented cytosolic mtDNA release and its colocalization with cGAS following irradiation. Cytosolic and extracellular mtDNA release was also induced in mouse upon whole-body irradiation. Our results demonstrated that mitochondrial damage signals spread throughout the body via exosomes or as cell-free DNA. Released mtDNA act as danger signals that trigger inflammation.
    Keywords:  Cytosolic DNA; Exosome; Mitochondrial DNA; Radiation; cGAS
    DOI:  https://doi.org/10.1038/s41598-025-04845-0
  2. Elife. 2025 Jun 30. pii: RP104461. [Epub ahead of print]14
    Tissue-specific responses to TFAM and mtDNA copy number manipulation in prematurely ageing mice.
    Laura Sophie Kremer, Guanbin Gao, Giovanni Rigoni, Roberta Filograna, Mara Mennuni, Rolf Wibom, Ákos Végvári, Camilla Koolmeister, Nils-Göran Larsson.
      Somatic mitochondrial DNA (mtDNA) mutations are implicated as important drivers of ageing and age-related diseases. Their pathological effect can be counteracted by increasing the absolute amount of wild-type mtDNA via moderately upregulating TFAM, a protein important for mtDNA packaging and expression. However, strong TFAM overexpression can also have detrimental effects as it results in mtDNA hypercompaction and subsequent impairment of mtDNA gene expression. Here, we have experimentally addressed the propensity of moderate TFAM modulation to improve the premature ageing phenotypes of mtDNA mutator mice, carrying random mtDNA mutations. Surprisingly, we detect tissue-specific endogenous compensatory mechanisms acting in mtDNA mutator mice, which largely affect the outcome of TFAM modulation. Accordingly, moderate overexpression of TFAM can have negative and beneficial effects in different tissues of mtDNA mutator mice. We see a similar behavior for TFAM reduction, which improves brown adipocyte tissue homeostasis, while other tissues are unaffected. Our findings highlight that the regulation of mtDNA copy number and gene expression is complex and causes tissue-specific effects that should be considered when modulating TFAM levels. Additionally, we suggest that TFAM is not the sole determinant of mtDNA copy number in situations where oxidative phosphorylation (OXPHOS) is compromised, but other important players must be involved.
    Keywords:  biochemistry; chemical biology; genetics; genomics; mitochondrial DNA; mouse; mtDNA copy number; mtDNA mutations; tissue specificity
    DOI:  https://doi.org/10.7554/eLife.104461
  3. Mol Cell. 2025 Jul 03. pii: S1097-2765(25)00505-2. [Epub ahead of print]85(13): 2610-2625.e5
    MLKL activates the cGAS-STING pathway by releasing mitochondrial DNA upon necroptosis induction.
    Zhangcheng Ding, Rui Wang, Yuhua Li, Xiaodong Wang.
      Necroptosis is a pro-inflammatory, lytic cell death executed by a pseudokinase mixed lineage kinase-like protein MLKL. Upon necroptosis induction by various inflammatory signals, MLKL is phosphorylated by receptor-interacting serine/threonine-protein kinase 3 (RIPK3) and translocates from the cytosol to the plasma membrane, causing membrane disruption and the release of damage-associated molecular patterns (DAMPs). We report here that phosphor-MLKL also translocates to mitochondria and induces a microtubule-dependent release of mitochondrial DNA (mtDNA). The released mtDNA activates the cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) pathway, resulting in the upregulation of interferon-beta (Ifnb) expression. In a necroptosis-mediated inflammatory bowel disease (IBD) mouse model, interfering with the cGAS-STING pathway reduced inflammation and promoted intestinal recovery. Thus, MLKL induces inflammation not only in a cell non-autonomous fashion by releasing DAMP signals, but also in a cell-autonomous manner by causing mtDNA leakage into the cytosol, thereby activating the cGAS-STING pathway.
    Keywords:  IBD; MLKL; cGAS; mitochondrail DNA; mitochondria; mtDNA; necroptosis
    DOI:  https://doi.org/10.1016/j.molcel.2025.06.005
  4. Nat Commun. 2025 Jul 01. 16(1): 5314
    A constricted mitochondrial morphology formed during respiration.
    Manish K Singh, Laetitia Cavellini, Maria Angeles Morcillo-Parra, Christina Kunz, Mickaël Lelek, Perrine Bomme, Aurélia Barascu, Cynthia Alsayyah, Maria Teresa Teixeira, Naïma Belgareh-Touzé, Adeline Mallet, Lea Dietrich, Christophe Zimmer, Mickael M Cohen.
      Mitochondria assemble in a dynamic tubular network. Their morphology is governed by mitochondrial fusion and fission, which regulate most mitochondrial functions including oxidative phosphorylation. Yet, the link between mitochondrial morphology and respiratgion remains unclear. Here, we uncover a mitochondrial morphology dedicated to respiratory growth of Saccharomyces cerevisiae, which we refer to as "Ringo". The Ringo morphology is characterized by stable constrictions of mitochondrial tubules. Ringo constrictions are mediated by the yeast dynamin Dnm1 and, unlike mitochondrial fission, occur in the absence of contacts with the endoplasmic reticulum. Our data show that blocking formation of the Ringo morphology correlates with decreased respiration, decreased expression of OXPHOS subunits and perturbed mitochondrial DNA distribution. These results open important perspectives about the link between mitochondrial form and function.
    DOI:  https://doi.org/10.1038/s41467-025-60658-9
  5. Trends Cancer. 2025 Jul 02. pii: S2405-8033(25)00153-0. [Epub ahead of print]
    mtDNA transfer from senescent cancer cells to MDSCs promotes immunosuppression.
    Israel Cañadas, Takahiko Murayama, Lorenzo Galluzzi.
      Sublethal apoptotic stress causing the permeabilization of some mitochondria coupled with cytosolic mitochondrial DNA (mtDNA) accumulation is known to promote cellular senescence. Lai et al. have recently demonstrated that this may be accompanied by mtDNA release within extracellular vesicles that promote local immunosuppression via myeloid-derived suppressor cells.
    Keywords:  NF-κB; PD-L1; SASP; STING; VDAC; prostate cancer
    DOI:  https://doi.org/10.1016/j.trecan.2025.06.010
  6. Nat Commun. 2025 Jul 01. 16(1): 5435
    Selfish mutations promote age-associated erosion of mtDNA integrity in mammals.
    Ekaterina Korotkevich, Daniel N Conrad, Zev J Gartner, Patrick H O'Farrell.
      Mutations in mitochondrial DNA (mtDNA) accumulate during aging and contribute to age-related conditions. High mtDNA copy number masks newly emerged recessive mutations; however, phenotypes develop when cellular levels of a mutant mtDNA rise above a critical threshold. The process driving this increase is unknown. Single-cell DNA sequencing of mouse and human hepatocytes detected increases in abundance of mutant alleles in sequences governing mtDNA replication. These alleles provided a replication advantage (drive) leading to accumulation of the affected genome along with a wide variety of associated passenger mutations, some of which are detrimental. The most prevalent human mtDNA disease variant, the 3243A>G allele, behaved as a driver, suggesting that drive underlies prevalence. We conclude that replicative drive amplifies linked mtDNA mutations to a threshold at which phenotypes are seen thereby promoting age-associated erosion of the mtDNA and influencing the transmission and progression of mitochondrial diseases.
    DOI:  https://doi.org/10.1038/s41467-025-60477-y
  7. Nat Commun. 2025 Jul 01. 16(1): 5460
    Autoregulation of the real-time kinetics of the human mitochondrial replicative helicase.
    Ismael Plaza-G A, María Ortiz-Rodríguez, Seth P Buchanan, Samuel Miguez-Amil, Kateryna M Lemishko, Fernando Moreno-Herrero, Rafael Fernandez-Leiro, Grzegorz L Ciesielski, Borja Ibarra.
      The human mitochondrial helicase Twinkle is essential for mitochondrial DNA (mtDNA) replication and integrity. Using biochemical and single-molecule techniques, we investigated Twinkle's real-time kinetics, including DNA loading, unwinding, and rewinding, and their regulation by its N-terminal Zinc-binding domain (ZBD), C-terminal tail, and mitochondrial SSB protein (mtSSB). Our results indicate that Twinkle rapidly scans dsDNA to locate the fork, where specific interactions halt diffusion. During unwinding, ZBD-DNA interactions and C-terminal tail control of ATPase activity downregulate kinetics, slowing down the helicase. Binding of mtSSB to DNA likely outcompetes ZBD-DNA interactions, alleviating the downregulatory effects of this domain. Furthermore, we show that ZBD-DNA interactions and ATP binding also regulate rewinding kinetics following helicase stalling. Our findings reveal that ZBD and C-terminal tail play a major role in regulation of Twinkle´s real-time kinetics. Their interplay constitutes an auto-regulatory mechanism that may be relevant for coordinating the mtDNA maintenance activities of the helicase.
    DOI:  https://doi.org/10.1038/s41467-025-60289-0
  8. Biochim Biophys Acta Mol Cell Res. 2025 Jun 30. pii: S0167-4889(25)00117-X. [Epub ahead of print]1872(7): 120012
    Mitochondrial DNA genotypes modify m.3243A>G-associated mitochondrial disease via the 15-HETE/Akt/FoxO1 pathway.
    Qian Wang, Chang You, Xiaoning Qu, YiQing Zhang, Yuxiao Bai, Xianlong Lin, Zhaoxia Wang, Hezhi Fang, Jianxin Lyu, Minghua Jiang, Ya Wang.
      Mitochondrial disease caused by mitochondrial DNA (mtDNA) 3243A>G mutation is characterized by high levels of clinical heterogeneity. Varied m.3243A>G mutation loads among patients are used to, but cannot fully explain, disease heterogeneity. Here, we found that mtDNA genotypes (haplogroups) modify m.3243A>G-associated natural selection and cell fate determination. mtDNA haplogroup M7 was less prevalent in a multi-center m.3243A>G disease cohort. Further functional studies using cybrids showed that M7 accelerated cell proliferation and shortened G0/G1 cell cycle when compared with cybrid carrying a non-M7 haplogroup (D5). However, mitochondrial function and cell viability were even worse in M7 cybrid than D5 cybrid when treated with mitochondrial oxidative phosphorylation (OXPHOS) inhibitors, indicating that M7 drives negative selection in patients with m.3243A>G during evolution. By adopting multi-omics strategies, we showed a lesser increase of 15-hydroxyeicosatetraenoic acid (15-HETE) levels in M7 cybrid owing to OXPHOS inhibition, leading to insufficient Akt/FoxO1 activation and increased apoptosis. Notably, 15-HETE administration activated Akt/FoxO1 phosphorylation and abolished apoptosis difference between M7 and D5 cybrids, suggesting that augmented 15-HETE was vital to protect cells from death. Collectively, our work identified a genetic modifier of m.3243A>G-associated mitochondrial disease and demonstrated that the mitochondrial retrograde 15-HETE/Akt/FOXO1 signaling cascade plays an important role in protecting cells from OXPHOS dysfunction-induced cell death.
    Keywords:  15-HETE; Akt-FoxO1 signaling; Mitochondrial disease; m.3243A>G; mtDNA haplogroup
    DOI:  https://doi.org/10.1016/j.bbamcr.2025.120012
  9. Nat Commun. 2025 Jul 04. 16(1): 6173
    Structural-functional characterization of the MIRO1-TRAK1 complex.
    Erika E Ravitch, Elana E Baltrusaitis, Tania A Perez, Kyle R Barrie, Adam R Fenton, Erika L F Holzbaur, Roberto Dominguez.
      Mitochondrial Rho GTPase (MIRO) features N- and C-terminal GTPase domains (nGTPase and cGTPase) flanking two pairs of EF-hands, and functions as a master scaffold on the outer mitochondrial membrane. It regulates mitochondrial motility by recruiting trafficking kinesin-binding protein (TRAK), which in turn recruits kinesin-1 and dynein-dynactin. The MIRO-TRAK interaction remains incompletely understood. Here, we describe the cryo-electron microscopy structure of TRAK1569-623 bound to MIRO1. The complex forms a dimer, mediated by interactions through the second EF-hand pair, cGTPase, and TRAK1. TRAK1569-623 binds in a cleft between the nGTPase and first EF-hand pair, inserting side chains into hydrophobic pockets of both domains. Another MIRO1-binding site involves TRAK1425-428, which binds in a pocket between the second EF-hand pair and cGTPase. Both binding sites are validated by mutagenesis and binding assays, showing no clear dependence on cofactor conditions (calcium or nucleotide). In cells, both sites contribute to TRAK1's mitochondrial localization.
    DOI:  https://doi.org/10.1038/s41467-025-61174-6
  10. Commun Biol. 2025 Jul 01. 8(1): 972
    An integrative modelling approach to the mitochondrial cristae.
    Chelsea M Brown, Marieke S S Westendorp, Rubi Zarmiento-Garcia, Jan A Stevens, Bart M H Bruininks, Sarah L Rouse, Siewert J Marrink, Tsjerk A Wassenaar.
      Mitochondria are implicated in many cellular functions such as energy production and apoptosis but also disease pathogenesis. To effectively perform these roles, the mitochondrial inner membrane has invaginations known as cristae that dramatically increase the surface area. This works to provide more space for membrane proteins that are essential to the roles of mitochondria. While separate components of this have been studied computationally, it remains a challenge to combine elements into an overall model. Here, we present a comprehensive model of a crista junction from a human mitochondrion and the accompanying workflow to construct it. Our coarse-grained representation of a crista shows how various experimentally determined features of organelles can be combined with molecular modelling to give insights into the interactions and dynamics of complicated biological systems. This work is presented as an initial 'living' model for this system, intended to be built upon and improved as our understanding, methodology and resources develop.
    DOI:  https://doi.org/10.1038/s42003-025-08381-5
  11. Nat Commun. 2025 Jul 01. 16(1): 5996
    The loss of OPA1 accelerates intervertebral disc degeneration and osteoarthritis in aged mice.
    Vedavathi Madhu, Miriam Hernandaz-Meadows, Ashley Coleman, Kimheak Sao, Kameron Inguito, Owen Haslam, Paige K Boneski, Hiromi Sesaki, Ruteja A Barve, John A Collins, Makarand V Risbud.
      Recent studies have highlighted the importance of mitochondria in NP cells and articular chondrocyte health. Since the understanding of mechanisms governing mitochondrial dynamics in these tissues is lacking, we investigated the role of OPA1, a mitochondrial fusion protein, in their homeostasis. OPA1 knockdown in NP cells altered mitochondrial size and cristae shape and increased the oxygen consumption rate. OPA1 governed the morphology of multiple organelles, including peroxisomes, early endosomes and cis-Golgi and loss resulted in the dysregulation of autophagy. Metabolic profiling and 13C-flux analyses revealed TCA cycle anaplerosis and altered metabolism in OPA1-deficient NP cells. Noteworthy, Opa1AcanCreERT2 mice showed age-dependent disc degeneration, osteoarthritis, and vertebral osteopenia. RNA-Sequencing of Opa1cKO NP tissue revealed dysregulation of metabolism, autophagy, cytoskeletal reorganization, and extracellular matrix and shared strong thematic similarities with a subset of human degenerative NP samples. Our findings underscore that maintenance of mitochondrial dynamics and multi-organelle cross-talk is critical in preserving metabolic homeostasis of disc and cartilage.
    DOI:  https://doi.org/10.1038/s41467-025-60933-9
  12. Nat Commun. 2025 Jul 02. 16(1): 6083
    Immuno-metabolic stress responses control longevity from mitochondrial translation inhibition in C. elegans.
    Iman Man Hu, Marte Molenaars, Yorrick R J Jaspers, Bauke V Schomakers, Michel van Weeghel, Amber Bakker, Melanie Modder, Joseph P Dewulf, Guido T Bommer, Arwen W Gao, Georges E Janssens, Riekelt H Houtkooper.
      Perturbing mitochondrial translation represents a conserved longevity intervention, with proteostasis processes proposed to mediate the resulting lifespan extension. Here, we explore whether other mechanisms may contribute to lifespan extension upon mitochondrial translation inhibition. Using multi-omics and functional in vivo screening, we identify the ethylmalonyl-CoA decarboxylase orthologue C32E8.9 in C. elegans as an essential factor for longevity induced by mitochondrial translation inhibition. Reducing C32E8.9 completely abolishes lifespan extension from mitochondrial translation inhibition, while mitochondrial unfolded protein response activation remains unaffected. We show that C32E8.9 mediates immune responses and lipid remodeling, which play crucial roles in the observed lifespan extension. Mechanistically, sma-4 (a TGF-β co-transcription factor) serves as an effector of C32E8.9, responsible for the immune response triggered by mitochondrial translation inhibition. Collectively, these findings underline the importance of the "immuno-metabolic stress responses" in longevity upon mitochondrial translation inhibition and identify C32E8.9 as a central factor orchestrating these responses.
    DOI:  https://doi.org/10.1038/s41467-025-61433-6
  13. Sci Rep. 2025 Jul 01. 15(1): 20678
    TRBP modulates RLR signaling by inhibiting PKR-mediated antiviral stress granule formation.
    Koji Onomoto, Monami Sakai, Miyu Watanabe, Akira Fukao, Yurika Sakamura, Mai Miyao, Takumi Tomohiro, Akio Yamashita, Toshinobu Fujiwara, Tomoko Takahashi, Kumiko Ui-Tei, Mitsutoshi Yoneyama.
      Stress granules (SGs) are dense aggregates of RNA and proteins that form in response to various cellular stresses. Virus-induced SGs, known as antiviral SGs (avSGs), play a crucial role in regulating retinoic acid-inducible gene I-like receptors (RLRs)-mediated antiviral innate immunity. However, the regulation of avSG formation remains not fully understood. In this study, we demonstrate that TAR-RNA binding protein (TRBP), an RNA silencing regulator, negatively regulates type I interferon (IFN) expression by inhibiting avSG formation in response to RNA virus infection. Overexpression of TRBP inhibits both IFN-β promoter activity and avSG formation following viral infection or the viral RNA mimic, polyinosinic-polycytidylic acid transfection. TRBP knockout cells exhibit enhanced phosphorylation and activation of IFN regulatory factor-3 (IRF-3) and increased IFN-β mRNA expression compared to wild-type cells. Additionally, depletion of G3BP1 and G3BP2, which are essential for SG formation, abolishes the inhibitory effect of TRBP on IRF-3 phosphorylation. Mechanistically, TRBP physically interacts with double-stranded RNA (dsRNA)-dependent protein kinase R (PKR), a key kinase involved in avSG formation, via its dsRNA-binding domains, and inhibits PKR activation. In summary, our findings reveal a novel function for TRBP as a negative regulator of RLR-mediated signaling through PKR-dependent inhibition of avSG formation.
    Keywords:  Antiviral innate immunity; IFN; RLR; Stress granule; TRBP
    DOI:  https://doi.org/10.1038/s41598-025-07121-3
  14. Cell Signal. 2025 Jul 01. pii: S0898-6568(25)00388-2. [Epub ahead of print] 111973
    High-throughput screening of E3 ubiquitin ligases identifies TRIM48 as a novel negative regulator of RIG-I signaling.
    Guandi Wu, Jamie Frankish, Joschka Willemsen, Dominik Ricken, Jonas Becker, Darius Schweinoch, Jürgen Beneke, Sandra Wüst, Nina Beil, Petr Matula, Karl Rohr, Holger Erfle, Lars Kaderali, Marco Binder.
      The retinoic acid-inducible gene-I (RIG-I) signaling is crucial for cell-intrinsic innate antiviral immunity. Upon cytosolic detection of virus-associated RNA, it triggers a cascade inducing production of potent cytokines, mainly type I and III interferons (IFNs). While effective, dysregulated responses can harm the host, requiring tight pathway control. Here, we performed a comprehensive, systematic siRNA-based high-throughput screen across 616 established and putative E3 ubiquitin ligases for their impact on RIG-I signaling. We employed a fluorescence-based live-cell imaging assay in A549 cells to monitor nuclear translocation of IRF3 and NF-κB, two key transcription factors downstream of RIG-I. Candidate genes were validated in an orthogonal secondary screen, assessing their impact on the functional antiviral response to a Rift Valley Fever reporter virus. Fourteen hits showed consistent effects on RIG-I signaling across both screens. These genes were further validated and characterized by assessing IFN-β promoter reporter activity and IFNB1 mRNA levels upon dsRNA transfection. TRIM48 emerged as a highly robust negative regulator. Overexpression of TRIM48 suppressed RIG-I-mediated activation of IRF3 and NF-κB, reduced IFN and IFN-stimulated gene expression, and enhanced viral replication. Conversely, TRIM48 deficiency enhanced RIG-I signaling and inhibited viral replication. Notably, TRIM48 acts as an induced feedback regulator upon infection, and its effect depended on its enzymatic ubiquitin ligase activity. Our high-throughput screen provides an unbiased assessment of close to all E3 ubiquitin ligases for their regulatory effect in RIG-I signaling, and identified several interesting candidates for further investigation. TRIM48 was established as a negative feedback regulator of the RIG-I pathway.
    Keywords:  E3 ubiquitin ligases; Innate antiviral immunity; RIG-I signaling; TRIM48; siRNA screening
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111973
  15. Sci Adv. 2025 Jul 04. 11(27): eadu3739
    Mitochondrial dysfunction enhances influenza pathogenesis by up-regulating de novo sialic acid biosynthesis.
    Amanda L Fuchs, Bharati Singh, Jillian W Jetmore, Emily B Warren, Payal Banerjee, Jose L Marin Franco, Michael A Eckhaus, Tatiana N Tarasenko, Madeleine R Assaad, Ivan Kosik, Jonathan Yewdell, Peter J McGuire.
      Mitochondrial dysfunction can trigger metabolic adaptations that resemble those induced by influenza A virus (IAV) infection. Here, we show that oxidative phosphorylation (OXPHOS) impairment, modeled by Ndufs4 deficiency, reprograms lung epithelial metabolism to promote IAV pathogenesis. In both Ndufs4 knockout (KO) mice and lung epithelial cells, OXPHOS deficiency increased glycolytic flux, diverting carbons into hexosamine and de novo sialic acid (SIA) biosynthesis pathways. This led to elevated sialylation and enhanced viral attachment. In Ndufs4 KO models, adenosine monophosphate-activated protein kinase signaling was insufficient to blunt this increased metabolic flux. IAV infection further exacerbated this metabolic vulnerability, amplifying SIA and viral burden. Pharmacologic rerouting of glucose carbons with dichloroacetate reduced sialylation, viral replication, and inflammatory responses in Ndufs4 KO models. These findings reveal that mitochondrial dysfunction enhances IAV susceptibility by disrupting energy sensing and fueling viral receptor biosynthesis, highlighting the importance of epithelial metabolism in viral pathogenesis and suggesting metabolic modulation as a potential therapeutic.
    DOI:  https://doi.org/10.1126/sciadv.adu3739
  16. Immunity. 2025 Jun 30. pii: S1074-7613(25)00275-4. [Epub ahead of print]
    Mitochondrial complex IV remodeling in tumor-associated macrophages amplifies interferon signaling and promotes anti-tumor immunity.
    Megan L Clark, Kamen P Simeonov, Walter K Mowel, Michaël F Michieletto, Leonel Joannas, Jasmine M Wright, Isabel Erickson, Lexus R Johnson, Rakesh Krishnan, César de la Fuente-Núñez, Andy J Minn, Jorge Henao-Mejia.
      Tumor-associated macrophages (TAMs) influence tumor progression and immune checkpoint blockade (ICB) efficacy. Interferon (IFN)-TAMs predict better survival and ICB responses, yet the mechanisms governing IFN-TAMs remain unclear. Here, we identify NDUFA4, a complex IV subunit of the electron transport chain, as a functional switch controlling TAM function and anti-tumor immunity. NDUFA4 expression sustained pro-tumoral TAMs. However, intratumoral IFNs decreased NDUFA4 expression in TAMs via the cooperative action of NDUFA4L3 and miR-147, co-encoded by a conserved bifunctional transcript. Mechanistically, NDUFA4 repression increased mitochondrial DNA release into the cytoplasm and subsequent STING activation, thereby amplifying anti-tumor IFN-induced transcriptional programs in TAMs. Finally, we designed RNA-based therapeutics that leveraged the specificity of miR-147 for the Ndufa4 transcript to enhance ICB efficacy and inhibit B16 melanoma tumor growth. These findings uncover mitochondrial complex IV remodeling as a critical mechanism governing the functional adaptation of macrophages to distinct microenvironments with broad implications for immunotherapy.
    Keywords:  STING; cGAS; complex IV; electron transport chain; immune checkpoint blockade; interferon-stimulated genes; mitochondria; tumor immunity; tumor microenvironment; tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.immuni.2025.06.006
  17. Sci Adv. 2025 Jul 04. 11(27): eadx4562
    Small molecule OPA1 inhibitors amplify cytochrome c release and reverse cancer cells resistance to Bcl-2 inhibitors.
    Anna Pellattiero, Charlotte Quirin, Federico Magrin, Mattia Sturlese, Alberto Fracasso, Nikolaos Biris, Stéphanie Herkenne, Laura Cendron, Evripidis Gavathiotis, Stefano Moro, Andrea Mattarei, Luca Scorrano.
      The guanosine triphosphatase (GTPase) activity of the mitochondrial dynamin-related protein Optic Atrophy 1 (OPA1) regulates cristae remodeling, cytochrome c release, and apoptosis. Elevated OPA1 levels in multiple cancers correlate with reduced therapy sensitivity and poor survival, calling for specific OPA1 GTPase inhibitors. A high-throughput screening of ~10,000 compounds identified MYLS22, a heterocyclic N-pyrazole derivative as a reversible, noncompetitive OPA1 GTPase inhibitor. MYLS22 engaged with OPA1 in vitro and in cells where it induced cristae remodeling and mitochondrial fragmentation contingent on intactness of its predicted OPA1 binding site. MYLS22 enhanced proapoptotic cytochrome c release and sensitized breast adenocarcinoma cells to anti-Bcl-2 therapy, without toxicity on noncancer cells. By MYLS22 structure-activity relationship studies, we obtained Opa1 inhibitor 0 (Opitor-0) that inhibited OPA1, promoted cytochrome c release, and restored anti-Bcl-2 therapy sensitivity more efficiently than MYLS22. These chemical probes validate OPA1 as a therapeutic target to increase cancer cell apoptosis at the mitochondrial level.
    DOI:  https://doi.org/10.1126/sciadv.adx4562
  18. Science. 2025 Jul 03. 389(6755): 84-91
    Membrane topology inversion of GGCX mediates cytoplasmic carboxylation for antiviral defense.
    Tomohiko Okazaki, Keiji Nozaki, Nao Morimoto, Yuta Otobe, Riho Saito, Shuntaro Abe, Miyuki Okajima, Hikari Yoshitane, Tomohisa Hatta, Shun-Ichiro Iemura, Tohru Natsume, Hidetaka Kosako, Miwako Yamasaki, Satoshi Inoue, Takashi Kondo, Haruhiko Koseki, Yukiko Gotoh.
      Mitochondrial antiviral signaling protein (MAVS) is an adaptor involved in antiviral immunity, but its regulation is not fully understood. We identified carboxylation of MAVS by vitamin K (VK)-dependent γ-glutamyl carboxylase (GGCX), which was unexpected owing to the reported membrane topology of GGCX. We found that GGCX could undergo topology inversion to carboxylate MAVS within the cytoplasm. This carboxylation enhanced the ability of MAVS to induce type I interferons while suppressing the induction of apoptosis. Genetic knockout of GGCX, a VK-free diet, or depletion of VK by inhibiting VK epoxide reductase 1 with warfarin increased viral susceptibility in mice. Thus, we identified a MAVS regulatory mechanism-the existence of cytoplasmic protein carboxylation and topological inversion of GGCX-and demonstrated how modulating VK levels may influence antiviral defense.
    DOI:  https://doi.org/10.1126/science.adk9967
  19. J Biol Chem. 2025 Jun 26. pii: S0021-9258(25)02280-X. [Epub ahead of print] 110430
    The ability of SAMHD1-deficient monocytes to trigger the type I IFN response depends on cGAS and mitochondrial DNA.
    Jesse Rabinowitz, Isabelle K Vila, Charlotte Luchsinger, Cinzia Bertelli, Moritz Schüssler, Clara Taffoni, Bin Cui, Annie Zhi Dai, Mohammad M Rashid, William J Cisneros, Daphne Cornish, Juan Redondo, Kathryn A Jackson-Jones, Lacy M Simons, Ramon Lorenzo-Redondo, Nadine Laguette, Judd F Hultquist, Felipe Diaz-Griffero.
      In humans, mutations in sterile α motif and histidine-aspartate domain-containing protein 1 (SAMHD1) lead to the development of a type I interferonopathy known as Aicardi-Goutières syndrome (AGS). AGS can present with a variety of severe phenotypes in patients, and a hallmark of this disease is chronic activation of type I interferon (IFN) signaling. However, the mechanism through which type I IFN signaling is activated in the absence of functional SAMHD1 is not known. Here, we investigated the molecular pathways that lead to type I IFN signaling activation in the absence of SAMHD1. Our investigations revealed that chronic activation of type I IFN signaling in SAMHD1-knockout(KO) monocytes is cyclic GMP-AMP synthase (cGAS)-dependent. Analysis of other nucleic acid sensors showed that type I IFN signaling in SAMHD1-KO cells is not dependent on melanoma differentiation-associated protein 5 (MDA5) or retinoic acid-inducible gene I (RIG-I). In agreement with our observation that type I IFN signaling is dependent on cGAS, two inhibitors of the cGAS-stimulator of IFN genes pathway, G140 and H151, effectively prevented type I IFN activation in SAMHD1-KO monocytes. We also found that type I IFN signaling in SAMHD1-KO monocytes is dependent on type I IFN receptor expression. Further exploration revealed mitochondrial malfunction in SAMHD1-KO monocytes that is likely to leak mitochondrial components into the cytoplasm. Overall, our work suggests that genetic knock out of SAMHD1 leads to mitochondrial disfunction, resulting in the presence of mitochondrial DNA in the cytoplasm, which triggers cGAS and the type I IFN response.
    Keywords:  Aicardi–Goutières syndrome; THP-1; cGAS; mitochondria; type I IFN response
    DOI:  https://doi.org/10.1016/j.jbc.2025.110430
  20. FEBS J. 2025 Jul 01.
    Human FASTK preferentially binds single-stranded and G-rich RNA.
    Daria M Dawidziak, Dawid A Dzadz, Mikołaj I Kuska, Madhuri Kanavalli, Maria M Klimecka, Matthew Merski, Katarzyna J Bandyra, Maria W Górna.
      Fas-activated serine/threonine kinase (FASTK) is the founding member of the FASTKD protein family, which was shown to regulate the fate of mRNA molecules on multiple levels. The mitochondrial variant of FASTK co-localizes with mitochondrial RNA granules and regulates the degradation of mitochondrial mRNAs, whereas the cytoplasmic and nuclear forms of FASTK are involved in the regulation of alternative splicing, cytoplasmic RNA granule formation, and mRNA translation. Despite these multiple roles of FASTK in mRNA biology, the exact rules of RNA recognition by this protein remained undetermined. Here, we demonstrate direct RNA binding by purified human FASTK and show its preference for single-stranded G-rich oligonucleotides, including those with a tendency to form RNA G-quadruplexes. Addition of FASTK alone was sufficient to achieve protection of mitochondrial mRNAs from degradation by the degradosome. Structural characterization by SAXS (Small-Angle X-ray Scattering) showed that FASTK in solution is a monomer with an extended conformation. Point mutagenesis studies supported the structural predictions of an exposed RNA-binding interface in the central helical region, preceded by a smaller, flexibly attached helical N-terminal domain. We provide the first such extensive in vitro characterization of the RNA binding properties for a representative of the FASTKD protein family and suggest how these intrinsic properties may underlie FASTK function in mRNA metabolism.
    Keywords:  FASTK; G‐rich RNA; RNA degradation; RNA‐binding proteins
    DOI:  https://doi.org/10.1111/febs.70155
  21. JCI Insight. 2025 Jul 03. pii: e192283. [Epub ahead of print]
    Cardiac Myocyte Cytosolic Self-DNA Contributes to the Pathogenesis of Desmoplakin-Cardiomyopathy.
    Weiyue Wang, Benjamin Cathcart, Quoc D Nguyen, Loi Q Lao, Amelia Bryans, Sara E Coleman, Leila Rouhi, Priyatansh Gurha, Ali J Marian.
      Hereditary cardiomyopathies are the prototypic forms of heart failure and major causes of sudden cardiac death. The genome in cardiomyopathies is exposed to internal stressors, which damage the DNA and activate the DNA damage response (DDR) pathways. We set to determine whether the DDR pathways were activated and pathogenic in an established mouse model of desmoplakin (DSP)-cardiomyopathy generated upon deletion of the Dsp gene in cardiac myocytes (Myh6-McmTam:DspF/F). The mice exhibited premature death, cardiac dysfunction, myocardial cell death, fibrosis, and increased expression levels of the pro-inflammatory cytokines, consistent with the phenotype of human DSP-cardiomyopathy. Cytosolic nuclear self-DNA (nDNA) and mitochondrial DNA (mtDNA) were increased in cardiac myocyte cytosol in the Myh6-McmTam:DspF/F mice. Likewise, the DDR pathway proteins, including the cyclic GMP-AMP synthase (CGAS), stimulator of interferon response 1 (STING1) were upregulated as were the transcript levels of interferon response factor 3 (IRF3) and the nuclear factor κB (NFκB) target genes. Deletion of the Mb21d1 gene encoding CGAS in the Myh6-McmTam:DspF/F mice prolonged survival, improved cardiac function, attenuated fibrosis, and reduced cell death. Thus, cytosolic nDNA and mtDNA are increased and the DDR pathways are activated and pathogenic in a mouse model of DSP-cardiomyopathy, whereas genetic blockade of CGAS is salubrious.
    Keywords:  Cardiology; Genetics; Heart failure
    DOI:  https://doi.org/10.1172/jci.insight.192283
  22. Front Immunol. 2025 ;16 1560104
    P-glycoprotein expression skews mitochondrial dye measurements in T cells.
    Sophia P M Sok, Jianan Cheng, Klaudia Strucinska, Narcis I Popescu, Lihua Wu, Qiuqing Ke, William B Kiosses, David Stanford, Willard M Freeman, Satoshi Matsuzaki, Tommy L Lewis, Meng Zhao.
      Assays to monitor metabolic parameters of immune cells at a single cell level provide efficient means to study immunometabolism. We show here that staining intensity of mitochondria targeting probes in T cells is dramatically influenced by P-glycoprotein/P-gp expression, a xenobiotic efflux pump that extrudes these fluorescent dyes. Discrepancies between MitoTracker Green FM/MTG signals and multiple dye-independent measurements are seen in CD4 T and CD8 T cell subsets and are corrected by P-gp inhibition (PSC833) during MTG staining. We further investigate invariant Natural Killer T (iNKT) cells, which express the highest level of P-glycoprotein among T cells. Using mtDNA abundance, mitochondrial volume, respiration and proteomics, we establish that iNKT cells have higher mitochondrial content and activity than CD4 T cells, opposite to what MTG signals reveal. A similar phenomenon is also seen in human PBMCs, and with TMRE, a dye indicator of mitochondrial membrane potential. Collectively, these data argue that P-glycoprotein expression is a significant confounding factor when analyzing T cells using mitochondrial specific dyes. Complementary methods are necessary to reliably assess mitochondrial features in T cells.
    Keywords:  P-glycolprotein; T cells; TMRE; mitochondria; mitotracker; oxidative phosphorilation
    DOI:  https://doi.org/10.3389/fimmu.2025.1560104
  23. Nature. 2025 Jul 02.
    WSTF nuclear autophagy regulates chronic but not acute inflammation.
    Yu Wang, Vinay V Eapen, Yaosi Liang, Athanasios Kournoutis, Marc Samuel Sherman, Yanxin Xu, Angelique Onorati, Xianting Li, Xiaoting Zhou, Kathleen E Corey, Kuo Du, Ana Maria Cabral Burkard, Chia-Kang Ho, Jing Xie, Hui Zhang, Raquel Maeso-Díaz, Xinyi Ma, Ulrike Rieprecht, Tara O'Brien, Murat Cetinbas, Lu Wang, Jihe Liu, Corey Bretz, Aaron P Havas, Zhuo Zhou, Shannan J Ho Sui, Srinivas Vinod Saladi, Ruslan I Sadreyev, Peter D Adams, Robert E Kingston, Anna Mae Diehl, Benjamin Alman, Wolfram Goessling, Zhenyu Yue, Xiao-Fan Wang, Terje Johansen, Zhixun Dou.
      Acute inflammation is an essential response that our bodies use to combat infections1. However, in the absence of infections, chronic inflammation can have a pivotal role in the onset and progression of chronic diseases, such as arthritis, cancer, autoimmune disorders, metabolic-dysfunction-associated steatohepatitis (MASH), and most ageing-associated pathologies2,3. The underlying mechanisms that distinguish chronic inflammation from its acute counterpart remain unclear, posing challenges to the development of targeted therapies for these major diseases. Here we identify a mechanism that separates the two responses: during chronic but not acute inflammation, chromatin remodelling is influenced by nuclear autophagy, in which the WSTF protein of the ISWI chromatin-remodelling complex interacts with the ATG8 autophagy protein family in the nucleus. This interaction leads to WSTF nuclear export and subsequent degradation by autophagosomes and lysosomes in the cytoplasm. Loss of WSTF leads to chromatin opening over inflammatory genes, amplifying inflammation. Cell-penetrating peptides that block the WSTF-ATG8 interaction do not affect acute inflammation but suppress chronic inflammation in senescence as well as in MASH and osteoarthritis in mouse models and patient samples. The ability to specifically target chronic inflammation without blunting acute inflammation offers an approach for treating common chronic inflammatory diseases.
    DOI:  https://doi.org/10.1038/s41586-025-09234-1
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